Paul B. Yu, MD, PhD

Summary of Research Project:

The Role of the BMP Type II Receptor in Vascular Function

Pulmonary hypertension is thought to originate in part from abnormal growth or maintenance of cells of the pulmonary vessels. Pulmonary vascular remodeling as such may lead to profound debilitation, right ventricular heart failure, the need for lung and/or heart transplantation, or death. A relatively recent development in this field was the identification of mutations in a single gene locus, the bone morphogenetic protein type II receptor (BMPR-II), in families with an inherited form of pulmonary hypertension. A major research effort is underway to understand the role of this receptor in pulmonary vascular development and maintenance, and its role in the disease of these afflicted families and in pulmonary hypertension in general. Our research has focused on a small animal model constructed to recapitulate the types of genetic mutations found in humans with the familial form of the disease. We have found that pulmonary vascular cells obtained from mice with BMPR-II mutations exhibit unexpected abnormalities in signaling. These abnormalities in signaling appear to lead to abnormal control of cell growth and differentiation in these cell types, and may contribute to the abnormal remodeling that leads to lesions of abnormally growing smooth muscle and endothelial cell types in diseased lung vessels. It is hoped that we can correlate these findings with a model of pulmonary hypertension in these same mutant mice. These cellular and animal models will help determine the precise pathways by which BMPR-II receptors and their signals affect the growth and developmental plan of pulmonary vessels. Understanding the role of BMPR-II in initiating disease could provide potential strategies for intercepting the disease or stopping its progression, and could provide a platform for testing these strategies.

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